SPECIFIC ADOPTIVE IMMUNOTHERAPY OF VIRAL DISEASES

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Studies performed since the last competitive renewal have demonstrated the feasibility of pursuing antigen-specific T cell therapy for treatment of human disease. Methods were developed for isolating and efficiently expanding in vitro CD4+ and CD8+ T cells clones with retention of normal function, and, in a Phase I trail; the adoptive transfer of large numbers of cloned CD8+ T cells specific for CMV was demonstrated to be non-toxic and to reconstitute deficient CD8+ T cell responses to CMV in immunodeficient bone marrow transplant (BMT) recipients. No patient with restored CD8+ T cell immunity developed CMV viremia or disease. In this project, we propose to use this T cell culture technology to determine if adoptive transfer of CMV-specific T cell clones can prevent early and late CMV infection in BMT recipients, and avoids toxicities associated with drug therapy. Several human tumors have been identified that express potentially immunogenic proteins. These include virus-associated malignancies, which provide attractive targets for immunologic therapies, since the viral proteins represent tumor-specific antigens. A subset of patients with Hodgkin's disease express several EBV latent proteins in their tumor cells, and studies are proposed to treat this human malignancy with EBV-specific T cell clones. The specific aims are: 1) to perform a Phase II study of adoptive immunotherapy with CMV-specific T cell clones as prophylaxis for CMV disease in recipients of allogeneic BMT from HLA-matched family members -- the study will include transfer of both cytolytic CD8+ and helper CD4= T cell clones and will examine therapeutic efficacy, immunologic reconstitution, and reduction in the frequency of neutropenia, a toxicity associated with ganciclovir prophylaxis; 2) to perform a Phase II study of adoptive immunotherapy with CMV-specific T cell clones for prevention of late CMV disease (> day + 100 post- BMT) in recipients of allogeneic BMT from HLA-matched unrelated donors--the study will evaluate therapeutic efficacy, long-term immunologic reconstitution, and the feasibility of generating T cells for therapy from unrelated donors; and 3) to evaluate the feasibility safety, and potential efficacy of treating Hodgkin's disease patients with EBV+ tumors by adoptive transfer of CD8+ T cell clones reactive with the EBV-encoded LMP1 or LMP2 proteins expressed in Reed- Sternberg cells -- this pilot study will examine safety, persistence, localization of transferred CD8+ clones to sites of tumor, and potential antitumor activity in patients undergoing autologous or allogeneic BMT for relapsed/resistant Hodgkins' disease.